Chemokines and Chemokine Receptors in the Development of Lupus Nephritis.
Lupus nephritis (LN) is a major cause of morbidity and mortality in the patients with systemic lupus erythematosus (SLE), an autoimmune disease with damage to multiple organs. Leukocyte recruitment into the inflamed kidney is a critical step to promote LN progression, and the chemokine/chemokine receptor system is necessary for leukocyte recruitment. In this review, we summarize recent studies on the roles of chemokines and chemokine receptors in the development of LN and discuss the potential and hurdles of developing novel, chemokine-based drugs to treat LN.


Neural mechanisms for the robust representation of junctions.
Junctions provide important cues in various perceptual tasks, such as the determination of occlusion relationships for figure-ground separation, transparency perception, and object recognition, among others. In computer vision, junctions are used in a number of tasks, like point matching for image tracking or correspondence analysis. We propose a biologically motivated approach to junction representation in which junctions are implicitly characterized by high activity for multiple orientations within a cortical hypercolumn. A local measure of circular variance is suggested to extract junction points from this distributed representation. Initial orientation measurements are often fragmented and noisy. A coherent contour representation can be generated by a model of V1 utilizing mechanisms of collinear long-range integration and recurrent interaction. In the model, local oriented contrast estimates that are consistent within a more global context are enhanced while inconsistent activities are suppressed. In a series of computational experiments, we compare junction detection based on the new recurrent model with a feedforward model of complex cells. We show that localization accuracy and positive correctness in the detection of generic junction configurations such as L- and T-junctions is improved by the recurrent long-range interaction. Further, receiver operating characteristics analysis is used to evaluate the detection performance on both synthetic and camera images, showing the superior performance of the new approach. Overall, we propose that nonlocal interactions implemented by known mechanisms within V1 play an important role in detecting higher-order features such as corners and junctions.


Heat-solubilized curry spice curcumin inhibits antibody-antigen interaction in in vitro studies: a possible therapy to alleviate autoimmune disorders.
Chronic and complex autoimmune diseases, currently treated palliatively with immunosuppressives, require multi-targeted therapy for greater effectiveness. The naturally occurring polyphenol curcumin has emerged as a powerful "nutraceutical" that interacts with multiple targets to regress diseases safely and inexpensively. Up to 8 g/day of curcumin for 18 months was non-toxic to humans. However, curcumin's utility is limited by its aqueous insolubility. We have demonstrated a heat-mediated 12-fold increase in curcumin's aqueous solubility. Here, we show by SDS-PAGE and surface plasmon resonance that heat-solubilized curcumin binds to proteins. Based on this binding we hypothesized that heat-solubilized curcumin or turmeric would prevent autoantibody targeting of cognate autoantigens. Heat-solubilized curcumin/turmeric significantly decreased binding of autoantibodies from Sjögren's syndrome (up to 43/70%, respectively) and systemic lupus erythematosus (up to 52/70%, respectively) patients as well as an animal model of Sjögren's syndrome (up to 50/60%, respectively) to their cognate antigens. However, inhibition was not specific to autoimmunity. Heat-solubilized curcumin/turmeric also inhibited binding of commercial polyclonal anti-spectrin to spectrin (50/56%, respectively). Thus, we suggest that the multifaceted heat-solubilized curcumin can ameliorate autoimmune disorders. In addition, the non-toxic curcumin could serve as a new protein stain in SDS-PAGE even though it is less sensitive than the Coomassie system which involves toxic chemicals.


Osteoid osteoma in the lumbar and sacral regions: two cases of difficult diagnosis.
We present two cases of osteoid osteoma affecting a lumbar vertebral body and the sacrum, being both in a very infrequent localization and difficult diagnosis. We found the scintigraphy to be of invaluable assistance in revealing the presence of this small nodular lesion of the spine, and the computed axial tomography (CAT) scan study was likewise useful for its precision in localizing the tumor as a basis for deciding upon a viable surgical approach. Without such techniques, correct diagnosis may be made too late. In our experience, surgical resection of the osteoid osteoma brings about immediate relief of the symptoms.


Invasive, mixed-type intraductal papillary mucinous neoplasm: superior prognosis compared to invasive main-duct intraductal papillary mucinous neoplasm.
It is unclear whether the duct involvement subtypes of intraductal papillary mucinous neoplasm (IPMN), ie, main (MD), mixed (MT), and branch (BD), confer any survival advantage when invasive IPMN occurs. We hypothesized that invasive MT-IPMN was associated with a better prognosis than invasive MD-IPMN. A retrospective review of a prospectively maintained database was performed of patients who underwent resection for IPMN at a single academic institution from 1992 to 2014. Characterization of IPMN subtype was assessed on final operative pathology. Statistics included univariate analysis, Kaplan-Meier survival curves, and Cox regression for independent predictors of increased survival. Of 390 patients eligible for study, 74 had invasive IPMN (IPMC). Of these, 71 patients had complete data and were included in the analysis (17 MD-IPMC, 39 MT-IPMC, and 15 BD-IPMC). Median follow-up was 20 months (range, 2-174). MT-IPMC was associated with significantly greater overall survival (OS) (47 months) compared with MD-IPMC (12 months) (P = .049), but not with BD-IPMC (44 months) (P = .67). Multivariate Cox regression yielded a family history of pancreatic cancer, absence of jaundice, N0 status, negative margins, absence of lymphovascular invasion, and MT subtype as independent predictors of greater OS (P = .035, .015, .013, .036, .045, .043, respectively). No characteristic of IPMN (including MD diameter, solid component/mural nodule) was predictive of OS. MT-IPMC appeared to be associated with a greater OS compared with pure MD-IPMC. This begs the question of a different underlying biology of MT-IPMN and argues against classification of all main duct involved IPMN into a single category.


The potential protective role of alpha-lipoic acid against acetaminophen-induced hepatic and renal damage.
The potential protective role of alpha-lipoic acid (alpha-LA) in acetaminophen (APAP)-induced hepatotoxicity and nephrotoxicity was investigated in rats. Pretreatment of rats with alpha-LA (100mg/kg) orally protected markedly against hepatotoxicity and nephrotoxicity induced by an acute oral toxic dose of APAP (2.5 g/kg) as assessed by biochemical measurements and by histopathological examination. None of alpha-LA pretreated animals died by the acute toxic dose of APAP. Concomitantly, APAP-induced profound elevation of nitric oxide (NO) production and oxidative stress, as evidenced by increasing of lipid peroxidation level, reducing of glutathione peroxidase (GSH-Px) activity and depleting of intracellular reduced glutathione (GSH) level in liver and kidney, were suppressed by pretreatment with alpha-LA. Similarly, daily treatment of rats with a smaller dose of alpha-LA (25mg/kg) concurrently with a smaller toxic dose of APAP (750 mg/kg) for 1 week protected against APAP-induced hepatotoxicity and nephrotoxicity. This treatment also completely prevented APAP-induced mortality and markedly inhibited APAP-induced NO overproduction and oxidative stress in hepatic and renal tissues. These results provide evidence that inhibition of NO overproduction and maintenance of intracellular antioxidant status may play a pivotal role in the protective effects of alpha-LA against APAP-induced hepatic and renal damage.


Genomic surveillance of Neisseria gonorrhoeae to investigate the distribution and evolution of antimicrobial-resistance determinants and lineages.
The first extensively drug resistant (XDR) Neisseria gonorrhoeae strain with high resistance to the extended-spectrum cephalosporin ceftriaxone was identified in 2009 in Japan, but no other strain with this antimicrobial-resistance profile has been reported since. However, surveillance to date has been based on phenotypic methods and sequence typing, not genome sequencing. Therefore, little is known about the local population structure at the genomic level, and how resistance determinants and lineages are distributed and evolve. We analysed the whole-genome sequence data and the antimicrobial-susceptibility testing results of 204 strains sampled in a region where the first XDR ceftriaxone-resistant N. gonorrhoeae was isolated, complemented with 67 additional genomes from other time frames and locations within Japan. Strains resistant to ceftriaxone were not found, but we discovered a sequence type (ST)7363 sub-lineage susceptible to ceftriaxone and cefixime in which the mosaic penA allele responsible for reduced susceptibility had reverted to a susceptible allele by recombination. Approximately 85 % of isolates showed resistance to fluoroquinolones (ciprofloxacin) explained by linked amino acid substitutions at positions 91 and 95 of GyrA with 99 % sensitivity and 100 % specificity. Approximately 10 % showed resistance to macrolides (azithromycin), for which genetic determinants are less clear. Furthermore, we revealed different evolutionary paths of the two major lineages: single acquisition of penA X in the ST7363-associated lineage, followed by multiple independent acquisitions of the penA X and XXXIV in the ST1901-associated lineage. Our study provides a detailed picture of the distribution of resistance determinants and disentangles the evolution of the two major lineages spreading worldwide.


A spatial evaluation of socio demographics surrounding National Priorities List sites in Florida using a distance-based approach.
Over the last two decades, various spatial techniques have been demonstrated using geographical information systems (GIS) to adequately estimate and characterize inequities of minority populations living near environmentally hazardous facilities. However, these methods have produced mixed results. In this study, we use recently developed variations of the "distance based" approach to spatially evaluate and compare demographic and socioeconomic disparities surrounding the worst hazardous waste sites in Florida. We used data from the 2000 US Census Bureau and the Florida Department of Environmental Protection to identify selected socio and economic variables within one (1) mile of 71 National Priorities List (NPL) or Superfund sites in Florida. ArcMap (ESRI, v. 9.2) was used to map the centroid locations of each of the NPL sites as well as identify and estimate the number of host and non-host tracts. The unit of analysis in this study was at the census tract level. Logistic regression (SAS v9.1.3) was used to determine if race/ethnicity and socioeconomic indicators are significant predictors of the location of NPL sites. There were significant differences in race/ethnicity composition and socio-economic factors between NPL host census tracts and non-host census tracts in Florida. The percentages of Blacks (OR = 5.7, p < 0.001), the percentage of Hispanic/Latino (OR = 5.84, p < 0.001), and percent employed in blue collar occupations (OR = 2.7, p < 0.01) were significant predictors of location of NPL facilities. The recently developed distance-based method supports previous studies and suggests that race and ethnicity play substantial roles in where hazardous facilities are located in Florida. Recommendations include using distance-based methods to evaluate socio and demographic characteristics surrounding other less known environmental hazardous facilities, such as landfills, or Toxic Release Inventory (TRI) sites.


Resting-State Brain Network Deficits in Multiple Sclerosis Participants: Evidence from Electroencephalography and Graph Theoretical Analysis.
Background: Multiple sclerosis (MS) is a chronic inflammatory disease leading to demyelination and axonal loss in the central nervous system that causes focal lesions of gray and white matter. However, the functional impairments of brain networks in this disease are still unspecified and need to be clearer. Materials and Methods: In the present study, we investigate the resting-state brain network impairments for MS participants in comparison to a normal group using electroencephalography (EEG) and graph theoretical analysis with a source localization method. Thirty-four age- and gender-matched participants from each MS group and normal group participated in this study. We recorded 5 min of EEG in the resting-state eyes open condition for each participant. One min (15 equal 4-sec artifact-free segments) of the EEG signals were selected for each participant, and the Low-Resolution Electromagnetic Tomography software was employed to calculate the functional connectivity among whole cortical regions in six frequency bands (delta, theta, alpha, beta1, beta2, and beta3). Graph theoretical analysis was used to calculate the clustering coefficient (CL), betweenness centrality (BC), shortest path length (SPL), and small-world propensity (SWP) for weighted connectivity matrices. Nonparametric permutation tests were utilized to compare these measures between groups. Results: Significant differences between the MS group and the normal group in the average of BC and SWP were found in the alpha band. The significant differences in the BC were spread over all lobes. Conclusion: These results suggest that the resting-state brain network for the MS group is disrupted in local and global scales, and EEG has the capability of revealing these impairments.


On the mechanism of preferential incorporation of dAMP at abasic sites in translesional DNA synthesis. Role of proofreading activity of DNA polymerase and thermodynamic characterization of model template-primers containing an abasic site.
DNA polymerase preferentially incorporate dAMP opposite abasic sites (A-rule). The mechanism of the A-rule can be studied by analyzing three dissected stages of the reaction including (i) initial nucleotide insertion, (ii) proofreading excision of the inserted nucleotide and (iii) extension of the nascent primer terminus. To assess the role of the stage (ii) in the A-rule, kinetic parameters of the proofreading excision of primer terminus nucleotides opposite abasic sites were determined using E.coli DNA polymerase I Klenow fragment. The relative efficiency of the excision (Vmax/Km) revealed that removal of A was the least favored of the four nucleotides, but the differences in the efficiencies between excision of A and the other nucleotides was less than 2-fold. In addition, in an attempt to reconcile kinetic data associated with the stage (i) or (ii), the differences in free energy changes (delta delta G degrees) for the formation of model template-primer termini containing XN pairs (X = abasic site, N = A, G, C or T) were determined by temperature dependent UV-melting measurements. The order of delta delta G degrees was XG > XA = XC > or = XT, with delta delta G degrees being 0.5 kcal/mol for the most stable XG and the least stable XT. Based on these data, the role of the stage (ii) and energetic aspects of the A-rule are discussed.


The long non-coding RNA nuclear-enriched abundant transcript 1_2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis.
A long non-coding RNA (lncRNA), nuclear-enriched abundant transcript 1_2 (NEAT1_2), constitutes nuclear bodies known as "paraspeckles". Mutations of RNA binding proteins, including TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS), have been described in amyotrophic lateral sclerosis (ALS). ALS is a devastating motor neuron disease, which progresses rapidly to a total loss of upper and lower motor neurons, with consciousness sustained. The aim of this study was to clarify the interaction of paraspeckles with ALS-associated RNA-binding proteins, and to identify increased occurrence of paraspeckles in the nucleus of ALS spinal motor neurons. In situ hybridization (ISH) and ultraviolet cross-linking and immunoprecipitation were carried out to investigate interactions of NEAT1_2 lncRNA with ALS-associated RNA-binding proteins, and to test if paraspeckles form in ALS spinal motor neurons. As the results, TDP-43 and FUS/TLS were enriched in paraspeckles and bound to NEAT1_2 lncRNA directly. The paraspeckles were localized apart from the Cajal bodies, which were also known to be related to RNA metabolism. Analyses of 633 human spinal motor neurons in six ALS cases showed NEAT1_2 lncRNA was upregulated during the early stage of ALS pathogenesis. In addition, localization of NEAT1_2 lncRNA was identified in detail by electron microscopic analysis combined with ISH for NEAT1_2 lncRNA. The observation indicating specific assembly of NEAT1_2 lncRNA around the interchromatin granule-associated zone in the nucleus of ALS spinal motor neurons verified characteristic paraspeckle formation. NEAT1_2 lncRNA may act as a scaffold of RNAs and RNA binding proteins in the nuclei of ALS motor neurons, thereby modulating the functions of ALS-associated RNA-binding proteins during the early phase of ALS. These findings provide the first evidence of a direct association between paraspeckle formation and a neurodegenerative disease, and may shed light on the development of novel therapeutic targets for the treatment of ALS.


Influence of the preparation conditions on the morphology of perylene thin films on Si(111) and Si(100).
Thin films of perylene on Si(111) and Si(100) substrates have been investigated using a variety of experimental techniques. We find that the structural and morphological properties as well as the growth modes strongly depend on the preparation parameters. In general, we observe the existence of a relatively weak coupling between perylene and the two single crystal substrates. However, under special preparation conditions, it is possible to obtain a multilayer phase on the Si(111) substrate that is characterized by flat-lying, parallel-oriented molecules, and strong coupling with the substrate in the first layer. This phase has different structural, electronic, and intermolecular bonding properties as compared to the known crystalline phases. On Si(100), by varying the deposition rate between 0.1 and 10 nm/min, it is possible to observe a transition from island growth mode, with large and isolated crystallites, to homogeneous film growth. These findings contribute to the basic knowledge for film engineering. Thus, the film morphology could be designed ranging from the growth of very large single grains suitable for a complete nanodevice to homogenous films for application in large displays.


Chronic Granulomatous Disease Presenting as Aspergillus Fumigatus Pneumonia in a Previously Healthy Young Woman.
BACKGROUND Chronic Granulomatous Disease (CGD) is a rare immunodeficiency disease caused by a genetic defect in the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase enzyme, resulting in increased susceptibility to bacterial and fungal infections. The inheritance can be X-linked or autosomal recessive. Patients usually present with repeated infections early in life. We present an unusual case of a 23-year-old patient diagnosed with CGD. CASE REPORT A 23-year-old white woman with no previous history of recurrent infections presented with complaints of fever, shortness of breath, and diffuse myalgia. She had been treated twice for similar complaints recently, but without resolution. She was febrile, tachypneic, tachycardic, and hypoxic at presentation. Physical examination revealed diffuse inspiratory rales. Laboratory results showed leukocytosis. Her initial chest X-ray and CT chest showed reticular nodular interstitial lung disease pattern. Despite being on broad-spectrum antibiotics for 5 days, she continued to require supplemental oxygen and continued to be tachypneic, with minimal activity. Initial diagnostic tests, including bronchoscopy with biopsy and lavage, did not reveal a diagnosis. She then underwent a video-assisted thoracoscopic surgery (VATS) lung biopsy. The biopsy slides showed suppurative granulomatous inflammation affecting greater than 50% of the parenchymal lung surface. Fungal hyphae consistent with Aspergillus were present in those granulomas. A diagnosis of CGD was made and she was started on Voriconazole. She improved with treatment. Her neutrophil burst test showed negative burst on stimulation, indicating phagocytic dysfunction consistent with CGD. Autosomal recessive CGD was confirmed by genetic testing. CONCLUSIONS CGD can present in adulthood without any previous symptoms and signs. Clinicians should consider this disease in patients presenting with recurrent or non-resolving infections. Timely treatment and prophylaxis has been shown to reduce serious infections as well as mortality in these patients.


Comparing students' feedback about clinical instruction with their performances.
Validation of students' feedback as a measure of teaching effectiveness has been problematic for courses teaching clinical skills. This is true in part because establishing a valid and reliable method of assessing students' mastery of clinical skills has been a stumbling block. Reported here is the correlation of students' performances on an objective structured clinical examination (OSCE) with previously and independently collected feedback from students. In 1987-88, 190 second-year medical students at the University of Minnesota Medical School--Minneapolis spent one fourth of a second-year clinical skills course on neurology randomly assigned to one of four teaching sites--hospitals A, B, C, and D. Following their rotations, 180 of the students completed usable feedback forms. The students were consistently and significantly more positive about the teaching at hospital A. At the end of the year, all 190 students were tested using an OSCE having 20 stations, four of which presented neurologic problems. The students who had the neurology course at hospital A performed better on all four neurology problems, and differences were statistically significant for two of the problems. Feedback in this case accurately reflected a more effective teaching program.


Nucleic Acids-based Nanotherapeutics Crossing the Blood Brain Barrier.
The restless endeavors revealing the molecular pathways underlying many neurodegenerative diseases and brain tumors have paved the way for the introduction of the selective exogenous gene-based therapeutics. The implicated active biomolecules encompass mainly negatively-charged nucleic acids ranging from DNA, mRNA, non-coding RNAs (small-interfering RNA, siRNA, and microRNA, miRNA), to antisense oligonucleotides. They selectively interfere with the genes translational and/or transcriptional processes. Although many reviews previously addressed brain targeting, a thorough correlation between the molecular properties of these biomacromolecules, the nature of blood brain barrier (BBB) in the accompanying pathological condition, the intracellular targets, as well as the design of the delivery system which will transport the bioactive cargo to the target cells attempting efficient delivery to the active sites in the brain will be appraised. In this review, we will further discuss the tremendous advances in non-viral gene delivery nanosystems currently investigated (starting from self-assembled nanoplexes using cationic polymers or lipids and going through liposomes, aptamers, polymersomes, exosomes, dendrimers and nanoparticles). Unlike previous reviews on this topic, functionalization strategies of the nanocarriers promoting either surface receptor binding or intracellular targeting of the cranial cells will be highlighted, with special emphasis on tailoring smart nanomedicines according to the CNS disease condition. In addition, newly-developed evaluation approaches, cell culture models studying BBB permeability and manipulation of the barrier function of the brain via focused ultrasound will be addressed.


Mushrooms: A rich source of the antioxidants ergothioneine and glutathione.
While mushrooms are the highest dietary source for the unique sulfur-containing antioxidant ergothioneine, little is known regarding levels of the major biological antioxidant glutathione. Thus, our objectives were to determine and compare levels of glutathione, as well as ergothioneine, in different species of mushrooms. Glutathione levels varied >20-fold (0.11-2.41mg/gdw) with some varieties having higher levels than reported for other foods. Ergothioneine levels also varied widely (0.15-7.27mg/gdw) and were highly correlated with those of glutathione (r=0.62, P<0.001). Both antioxidants were more concentrated in pileus than stipe tissues in selected mushrooms species. Agaricus bisporus harvested during the third cropping flush contained higher levels of ergothioneine and glutathione compared to the first flush, possibly as a response to increased oxidative stress. This study demonstrated that certain mushroom species are high in glutathione and ergothioneine and should be considered an excellent dietary source of these important antioxidants.


Estrogen directly activates AID transcription and function.
The immunological targets of estrogen at the molecular, humoral, and cellular level have been well documented, as has estrogen's role in establishing a gender bias in autoimmunity and cancer. During a healthy immune response, activation-induced deaminase (AID) deaminates cytosines at immunoglobulin (Ig) loci, initiating somatic hypermutation (SHM) and class switch recombination (CSR). Protein levels of nuclear AID are tightly controlled, as unregulated expression can lead to alterations in the immune response. Furthermore, hyperactivation of AID outside the immune system leads to oncogenesis. Here, we demonstrate that the estrogen-estrogen receptor complex binds to the AID promoter, enhancing AID messenger RNA expression, leading to a direct increase in AID protein production and alterations in SHM and CSR at the Ig locus. Enhanced translocations of the c-myc oncogene showed that the genotoxicity of estrogen via AID production was not limited to the Ig locus. Outside of the immune system (e.g., breast and ovaries), estrogen induced AID expression by >20-fold. The estrogen response was also partially conserved within the DNA deaminase family (APOBEC3B, -3F, and -3G), and could be inhibited by tamoxifen, an estrogen antagonist. We therefore suggest that estrogen-induced autoimmunity and oncogenesis may be derived through AID-dependent DNA instability.


Hexagonal phase with ordered acyl chains formed by a short chain asymmetric ceramide.
Ceramides constitute a group of lipids with usually high melting temperature that also favor negative curvature in membranes when mixed with other lipids. The short chain C10:0 ceramide is an asymmetric lipid which consists of an 18 carbon sphingosine base N-acylated with decanoic acid. According to high sensitivity differential scanning calorimetry, it shows a minor exothermic peak at 61°C and a main endothermic transition at 75°C. By small angle X-ray scattering and polarized light microscopy we found that, at temperatures below the main transition, the fully hydrated lipid dispersions are arranged in a tridimensional structure corresponding to an inverted hexagonal phase. Infrared spectroscopy and wide angle X-ray diffraction indicated that the acyl chains of ceramides exhibit a relatively high order in the hexagonal phase. As far as we know, this is the first report of a lipid hexagonal phase having highly ordered acyl chains. Molecular asymmetry due to the different length of the sphingosine and the N-acyl chains of C10:0 ceramide may explain why this novel phase is formed.


Enhancer divergence and cis-regulatory evolution in the human and chimp neural crest.
cis-regulatory changes play a central role in morphological divergence, yet the regulatory principles underlying emergence of human traits remain poorly understood. Here, we use epigenomic profiling from human and chimpanzee cranial neural crest cells to systematically and quantitatively annotate divergence of craniofacial cis-regulatory landscapes. Epigenomic divergence is often attributable to genetic variation within TF motifs at orthologous enhancers, with a novel motif being most predictive of activity biases. We explore properties of this cis-regulatory change, revealing the role of particular retroelements, uncovering broad clusters of species-biased enhancers near genes associated with human facial variation, and demonstrating that cis-regulatory divergence is linked to quantitative expression differences of crucial neural crest regulators. Our work provides a wealth of candidates for future evolutionary studies and demonstrates the value of "cellular anthropology," a strategy of using in-vitro-derived embryonic cell types to elucidate both fundamental and evolving mechanisms underlying morphological variation in higher primates.


Altered cardiac responsiveness and regulation in the normal cardiac output type of borderlind hlpertension.
Of 145 patients with borderline hypertension, 30% had increased resting cardiac index (QI), whereas the remainder had normal values. The specific aim of this study was to investigate cardiac regulation in patients who had normal resting QI. Eighty-five control subjects were used for comparison. At rest, patients with normal QI showed evidence of decreased parasympathetic inhibition; the QI after injection of atropine increased less than in control subjects. After complete cardiac autonomic blockade with propranolol and atropine, QI and stroke volume were significantly lower in patients than in control subjects. The mechanism of this low QI was further analyzed. Central blood volume, which strongly correlates with stroke volume, was used as an estimate of the cardiac venous filling. After blockade, stroke volume was decreased in patients, but central blood volume was normal. Patients also showed a decreased heart rate and QI response to infusion of isoproterenol. It is therefore postulated that two components may be responsible for the low QI in the "denervated" heart: patients exhibit a decreased responsiveness to sympathetic stimulation, and they may also be less responsive to venous filling. Behind the facade of cardiac normality in these borderline hypertensive patients with normal cardiac output, there is evidence of altered autonomic control of the heart (decreased vagal inhibition) and of changed cardiac response to sympathetic stimulation and possibly to venous filling.


Large positive and negative lateral shifts near pseudo-Brewster dip on reflection from a chiral metamaterial slab.
The lateral shifts from a slab of lossy chiral metamaterial are predicted for both perpendicular and parallel components of the reflected field, when the transverse electric (TE)-polarized incident wave is applied. By introducing different chirality parameter, the lateral shifts can be large positive or negative near the pseudo-Brewster angle. It is found that the lateral shifts from the negative chiral slab are affected by the angle of incidence and the chirality parameter. In the presence of inevitable loss of the chiral slab, the enhanced lateral shifts will be decreased, and the pseudo-Brewster angle will disappear correspondingly. For the negative chiral slab with loss which is invisible for the right circularly polarized (RCP) wave, we find that the loss of the chiral slab will lead to the fluctuation of the lateral shift with respect to the thickness of the chiral slab.The validity of the stationary-phase analysis is demonstrated by numerical simulations of a Gaussian-shaped beam.


Fat digestion and absorption in spice-pretreated rats.
A few common spices are known to stimulate secretion of bile with higher amount of bile acids which play a major role in digestion and absorption of dietary lipids. It would be appropriate to verify if these spices enable efficient digestion and absorption during high-fat intake. In this context, dietary ginger (0.05%), piperine (0.02%), capsaicin (0.015%), and curcumin (0.5%) were examined for their influence on bile secretion, digestive enzymes of pancreas and absorption of dietary fat in high-fat (30%) fed Wistar rats for 8 weeks. These spices enhanced the activity of pancreatic lipase, amylase, trypsin and chymotrypsin by 22-57%, 32-51%, 63-81% and 12-38%, respectively. Dietary intake of spices along with high-fat enhanced fat absorption. These dietary spices increased bile secretion with higher bile acid content. Stimulation of lipid mobilisation from adipose tissue was suggested by the decrease in perirenal adipose tissue weight by dietary capsaicin and piperine. This was also accompanied by prevention of the accumulation of triglyceride in liver and serum in high-fat fed rats. Activities of key lipogenic enzymes in liver were reduced which was accompanied by an increased activity of hormone-sensitive lipase. Thus, dietary ginger and other spice compounds enhance fat digestion and absorption in high-fat fed situation through enhanced secretion of bile salts and a stimulation of the activity pancreatic lipase. At the same time, the energy expenditure is facilitated by these spices to prevent the accumulation of absorbed fat.


Nanostructures and hydrophilicity influence osseointegration: a biomechanical study in the rabbit tibia.
Implant surface properties have long been identified as an important factor to promote osseointegration. The importance of nanostructures and hydrophilicity has recently been discussed. The aim of this study was to investigate how nanostructures and wettability influence osseointegration and to identify whether the wettability, the nanostructure or both in combination play the key role in improved osseointegration. Twenty-six adult rabbits each received two Ti grade 4 discs in each tibia. Four different types of surface modifications with different wettability and nanostructures were prepared: hydrophobic without nanostructures (SLA), with nanostructures (SLAnano); hydrophilic with two different nanostructure densities (low density: pmodSLA, high density: SLActive). All four groups were intended to have similar chemistry and microroughness. The surfaces were evaluated with contact angle measurements, X-ray photoelectron spectroscopy, scanning electron microscopy, atomic force microscopy and interferometry. After 4 and 8 weeks healing time, pull-out tests were performed. SLA and SLAnano were hydrophobic, whereas SLActive and pmodSLA were super-hydrophilic. No nanostructures were present on the SLA surface, but the three other surface modifications clearly showed the presence of nanostructures, although more sparsely distributed on pmodSLA. The hydrophobic samples showed higher carbon contamination levels compared with the hydrophilic samples. After 4 weeks healing time, SLActive implants showed the highest pull-out values, with significantly higher pull-out force than SLA and SLAnano. After 8 weeks, the SLActive implants had the highest pull-out force, significantly higher than SLAnano and SLA. The strongest bone response was achieved with a combination of wettability and the presence of nanostructures (SLActive).


Multitargeted tyrosine kinase inhibition produces discordant changes between 99mTc-MDP bone scans and other disease biomarkers: analysis of a phase II study of sunitinib for metastatic castration-resistant prostate cancer.
One of the central unanswered questions in prostate cancer research is the significance of tyrosine kinase inhibitor (TKI)-induced improvements in (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) bone scans. Multitargeted tyrosine kinase inhibition has recently shown promise in the management of castration-resistant prostate cancer. In some cases, TKI inhibition has produced unprecedented improvements in bone metastases as detected by (99m)Tc-MDP bone scans. The significance of these improvements is not known. In order to gain insight about the effects of TKIs on bone scans in prostate cancer, we systematically evaluated images from a phase II study of sunitinib, a multitargeted TKI. We analyzed images and data from a previously reported open-label phase II study that enrolled 34 men with advanced castration-resistant prostate cancer. Participants received sunitinib in 6-wk cycles (50 mg daily; 4 wk on, 2 wk off). We examined baseline and 12-wk bone scan images. Partial response was defined as an improvement of at least 50% in previous metastatic lesions subjectively or a change from prior diffuse skeletal metastases (superscan) to recognizable individual metastatic lesions. Our primary objective was to define the incidence of at least partial bone scan response. We also examined concomitant changes in CT and prostate-specific antigen (PSA) evidence of disease. Analysis at 12 wk revealed 1 partial response by the response evaluation criteria in solid tumors (RECIST) and 2 confirmed PSA responses. There were 25 subjects who underwent bone scans at both time points (baseline and week 12) and who had bone metastases detectable at baseline. Within that group of 25, we found 5 bone scan partial responses and 1 complete response. None of those 6 subjects exhibited a PSA response (≥50% decline from baseline) or RECIST response. We found a relatively high rate of (99m)Tc-MDP bone scan response to sunitinib among men with metastatic prostate cancer. Further, we found that none of the subjects exhibiting bone scan responses experienced concordant improvements in PSA or CT evidence of disease by accepted criteria. This discordance argues that osteoblastic assessment provides an incomplete assessment of treatment-induced changes. Rational development of multitargeted TKIs for prostate cancer requires improved understanding of treatment-induced bone scan changes. Optimal imaging strategies may include evaluation of perfusion or direct tumor activity.


Critical appraisal of Rome IV criteria: hypersensitive esophagus does belong to gastroesophageal reflux disease spectrum.
The Rome IV Committee introduced a major change in the classification of functional gastrointestinal disorders, proposing a more restrictive definition of gastroesophageal reflux disease (GERD). It was suggested that hypersensitive esophagus (HE) may sit more firmly within the functional realm. It was suggested that GERD diagnosis should be based upon abnormal acid exposure time (AET) only, implying no advantage of impedance-pH over pH monitoring. Symptom association probability (SAP), symptom index (SI) and heartburn relief with proton pump inhibitor (PPI) therapy were regarded as unreliable, whereas a lack of response to PPI was considered as evidence of functional heartburn. These assumptions are contradicted by numerous studies showing the clinical relevance of weakly acidic refluxes and the diagnostic utility of SAP, SI and new impedance parameters, namely the post-reflux swallow-induced peristaltic wave (PSPW) index and the mean nocturnal baseline impedance (MNBI). The PSPW index and MNBI provide significant diagnostic advantage, particularly in patients with normal AET who can be classified as HE when both parameters are abnormal, even though SAP and SI are negative. Visceral pain modulators are recommended by the Rome IV Committee despite scanty evidence of efficacy, but a positive outcome with medical or surgical anti-reflux treatment has been reported by several studies of HE patients. Therefore, we believe that patients with endoscopy-negative heartburn should be investigated by means of impedance-pH monitoring with analysis of PSPW index and MNBI: such an approach provides accurate identification of HE cases, who remain, in our opinion, within the realm of GERD and should be treated accordingly.


Identification and expression analysis of diapause hormone and pheromone biosynthesis activating neuropeptide (DH-PBAN) in the legume pod borer, Maruca vitrata Fabricius.
Neuropeptides play essential roles in a variety of physiological responses that contribute to the development and reproduction of insects. Both the diapause hormone (DH) and pheromone biosynthesis activating neuropeptide (PBAN) belong to the PBAN/pyrokinin neuropeptide family, which has a conserved pentapeptide motif FXPRL at the C-terminus. We identified the full-length cDNA encoding DH-PBAN in Maruca vitrata, a major lepidopteran pest of leguminous crops. The open reading frame of Marvi-DH-PBAN is 591 bp in length, encoding 197 amino acids, from which five putative neuropeptides [DH, PBAN, α-subesophageal ganglion neuropeptide (SGNP), β-SGNP and γ-SGNP] are derived. Marvi-DH-PBAN was highly similar (83%) to DH-PBAN of Omphisa fuscidentalis (Lepidoptera: Crambidae), but possesses a unique C-terminal FNPRL motif, where asparagine has replaced a serine residue present in other lepidopteran PBAN peptides. The genomic DNA sequence of Marvi-DH-PBAN is 6,231 bp in size and is composed of six exons. Phylogenetic analysis has revealed that the Marvi-DH-PBAN protein sequence is closest to its homolog in Crambidae, but distant from Diptera, Coleoptera and Hymenoptera DH-PBAN, which agrees with the current taxonomy. DH-PBAN transcripts were present in the head and thoracic complex, but absent in the abdomen of M. vitrata. Real-time quantitative PCR assays have demonstrated a relatively higher expression of Marvi-DH-PBAN mRNA in the latter half of the pupal stages and in adults. These findings represent a significant step forward in our understanding of the DH-PBAN gene architecture and phylogeny, and raise the possibility of using Marvi-DH-PBAN to manage M. vitrata populations through molecular techniques.


The role of ZAP and OAS3/RNAseL pathways in the attenuation of an RNA virus with elevated frequencies of CpG and UpA dinucleotides.
Zinc finger antiviral protein (ZAP) is a powerful restriction factor for viruses with elevated CpG dinucleotide frequencies. We report that ZAP similarly mediates antiviral restriction against echovirus 7 (E7) mutants with elevated frequencies of UpA dinucleotides. Attenuation of both CpG- and UpA-high viruses and replicon mutants was reversed in ZAP k/o cell lines, and restored by plasmid-derived reconstitution of expression in k/o cells. In pull-down assays, ZAP bound to viral RNA transcripts with either CpG- and UpA-high sequences inserted in the R2 region. We found no evidence that attenuation of CpG- or UpA-high mutants was mediated through either translation inhibition or accelerated RNA degradation. Reversal of the attenuation of CpG-high, and UpA-high E7 viruses and replicons was also achieved through knockout of RNAseL and oligodenylate synthetase 3 (OAS3), but not OAS1. WT levels of replication of CpG- and UpA-high mutants were observed in OAS3 k/o cells despite abundant expression of ZAP, indicative of synergy or complementation of these hitherto unconnected pathways. The dependence on expression of ZAP, OAS3 and RNAseL for CpG/UpA-mediated attenuation and the variable and often low level expression of these pathway proteins in certain cell types, such as those of the central nervous system, has implications for the use of CpG-elevated mutants as attenuated live vaccines against neurotropic viruses.


Direct inguinal hernias and anterior surgical approach are risk factors for female inguinal hernia recurrences.
The purpose of this study was to establish the risk of recurrence after direct and indirect inguinal hernia operation in a large-scale female population and to establish the relationship between the type of hernia at the primary and recurrent procedure. Using data from the Danish Hernia Database (DHDB), a cohort was generated: all females operated on electively for a primary inguinal hernia by either Lichtenstein's technique or laparoscopy from 1998 to 2012. Within this prospectively collected cohort, the hernia type at the primary procedure (direct inguinal hernia (DIH), indirect inguinal hernia (IIH), combination hernia), the hernia type at the recurrent procedure (DIH, IIH, combination hernia, femoral hernia), anesthesia type, and time from primary procedure to reoperation were registered. A total of 5,893 females with primary elective inguinal hernia operation on in the study period (61 % IIH, 37 % DIH, 2 % combined hernias) were included with a median follow-up time of 72 months (range 0 to 169). A total of 305 operations for suspected recurrences were registered (61 % inguinal recurrences, 38 % femoral recurrences, 1 % no hernias), which corresponded to an overall reoperation rate of 5.2 %. All femoral recurrences occurred after a previous open anterior operation. The crude reoperation rate after primary DIH operation was 11.0 %, 3.0 % after primary IIH operation and 0.007 % after combined hernia operation (p < 0.001). The multivariate adjusted analysis found that DIH at primary operation was a substantial risk factor for recurrence with a hazard ratio of 3.1 (CI 95 % 2.4–3.9) compared with IIH at primary operation (p < 0.001), and that laparoscopic operation gave a lower risk of recurrence with a hazard ratio of 0.57 (CI 95 % 0.43–0.75) compared with Lichtenstein's technique (p < 0.001). The risk of femoral recurrence was correlated to operation for DIH with a hazard ratio of 2.4 (CI 95 % 1.7–3.5) compared with operation for IIH. In a female nationwide prospectively gathered cohort, we found that operation for a DIH resulted in a higher risk of reoperation than operation for an IIH. We found that femoral hernia recurrences exclusively existed after anterior open primary operation.


Drone vs. Bird Detection: Deep Learning Algorithms and Results from a Grand Challenge.
Adopting effective techniques to automatically detect and identify small drones is a very compelling need for a number of different stakeholders in both the public and private sectors. This work presents three different original approaches that competed in a grand challenge on the "Drone vs. Bird" detection problem. The goal is to detect one or more drones appearing at some time point in video sequences where birds and other distractor objects may be also present, together with motion in background or foreground. Algorithms should raise an alarm and provide a position estimate only when a drone is present, while not issuing alarms on birds, nor being confused by the rest of the scene. In particular, three original approaches based on different deep learning strategies are proposed and compared on a real-world dataset provided by a consortium of universities and research centers, under the 2020 edition of the Drone vs. Bird Detection Challenge. Results show that there is a range in difficulty among different test sequences, depending on the size and the shape visibility of the drone in the sequence, while sequences recorded by a moving camera and very distant drones are the most challenging ones. The performance comparison reveals that the different approaches perform somewhat complementary, in terms of correct detection rate, false alarm rate, and average precision.


Evidence That Lifelong Low Dose Rates of Ionizing Radiation Increase Lifespan in Long- and Short-Lived Dogs.
After the 1956 radiation scare to stop weapons testing, studies focused on cancer induction by low-level radiation. Concern has shifted to protecting "radiation-sensitive individuals." Since longevity is a measure of health impact, this analysis reexamined data to compare the effect of dose rate on the lifespans of short-lived (5% and 10% mortality) dogs and on the lifespans of dogs at 50% mortality. The data came from 2 large-scale studies. One exposed 10 groups to different γ dose rates; the other exposed 8 groups to different lung burdens of plutonium. Reexamination indicated that normalized lifespans increased more for short-lived dogs than for average dogs, when radiation was moderately above background. This was apparent by interpolating between the lifespans of nonirradiated dogs and exposed dogs. The optimum lifespan increase appeared at 50 mGy/y. The threshold for harm (decreased lifespan) was 700 mGy/y for 50% mortality dogs and 1100 mGy/y for short-lived dogs. For inhaled α-emitting particulates, longevity was remarkably increased for short-lived dogs below the threshold for harm. Short-lived dogs seem more radiosensitive than average dogs and they benefit more from low radiation. If dogs model humans, this evidence would support a change to radiation protection policy. Maintaining exposures "as low as reasonably achievable" (ALARA) appears questionable.


Gene expression regulating epithelial intercellular junction biogenesis during human blastocyst development in vitro.
We investigated gene expression associated with trophectoderm epithelial intercellular junction formation in single human embryos at different stages of cleavage using RT-PCR methods based upon magnetic bead separation of polyA+ RNA. Trophectoderm tight junction (TJ) and desmosome biogenesis contribute to intercellular sealing and tissue integrity, critical for vectorial transport and blastocoel cavity formation. Expression of the various genes throughout human preimplantation development showed differing levels of sensitivity of detection; these genes included claudin-1, occludin (TM4+ and TM4 isoforms), ZO-1 (ZO-1alpha+ and ZO-1alpha- isoforms), ZO-2 and JAM (junction adhesion molecule), and the desmosome junction gene, DSC2 (desmocollin 2). Some transcripts appeared to be expressed throughout preimplantation development (claudin-1, JAM, occludin TM4+ and TM4, ZO-1alpha- isoform) while others tended to be expressed preferentially in later cleavage and associated with blastocyst formation (ZO-2, ZO-1alpha+ isoform, DSC-2), illustrating an expression pattern broadly similar to mouse cleavage stages. Human embryo transcript detection was significantly decreased when reverse transcription was performed in solid phase to generate a bead/cDNA transient library rather than after mRNA elution from beads. Transcript detection tended to be positively correlated with embryo morphological grade using the solid phase method. In blastocysts, occludin TM4-, ZO-1alpha+ and DSC2 transcripts were the most susceptible to failure of detection, indicative of low levels of expression which may impact on trophectoderm differentiation competence. Immunoconfocal microscopy analysis of selected adhesion and TJ proteins in human embryos indicated poor membrane assembly compared with mouse blastocysts, which may further affect embryo viability.


Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice.
Aging is a contributing factor in cancer occurrence. We recently demonstrated that systemic immunotherapy (IT) administration in aged, but not young, mice resulted in induction of rapid and lethal cytokine storm. We found that aging was accompanied by increases in visceral fat similar to that seen in young obese (ob/ob or diet-induced obese [DIO]) mice. Yet, the effects of aging and obesity on inflammatory responses to immunotherapeutics are not well defined. We determine the effects of adiposity on systemic IT tolerance in aged compared with young obese mice. Both young ob/ob- and DIO-generated proinflammatory cytokine levels and organ pathologies are comparable to those in aged ad libitum mice after IT, culminating in lethality. Young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNF(+) macrophages in response to αCD40/IL-2 as compared with young lean mice. Macrophage depletion or TNF blockade in conjunction with αCD40/IL-2 prevented cytokine storms in young obese mice and protected from lethality. Calorie-restricted aged mice contain less visceral fat and displayed reduced cytokine levels, protection from organ pathology, and protection from lethality upon αCD40/IL-2 administration. Our data demonstrate that adiposity is a critical factor in the age-associated pathological responses to systemic anti-cancer IT.


Bias of vaccination coverage in a household questionnaire survey in Japan.
Although a household questionnaire survey is important for estimating vaccination coverage, it raises several problematic issues. A household survey was conducted on 900 subjects aged 2, 4, and 6 years living in Obu City, Japan, and a second survey for non-respondents to the first survey was then conducted. Questionnaires bearing a subject's name were used for half of the subjects, while the others were anonymous (the named and nameless groups, respectively). The vaccination dates of six kinds of vaccines, including poliovirus and measles vaccine, for those in the named group were reviewed using the administrative records at the Obu City Health Center. The response rate was 70.1% in the first survey and 84.1% in the first and second surveys combined. The response rate for both groups was nearly equal. Based on administrative records in the named group, the vaccination coverage in the respondents was 0.9-2.9% higher than that in total subjects, and that in the respondents to the first survey was 0.8-4.9% higher. There were very few inconsistencies in the vaccination status between responses to the questionnaire and data of administrative records among respondents in the named group. These results suggested that vaccination coverage from a household questionnaire survey in Japan might not be extremely biased by either non-responses or incorrect answers.


Esophageal Metal Stents with Concurrent Chemoradiation Therapy for Locally Advanced Esophageal Cancer: Safe or Not?
The purpose of this study was to review the risks and benefits of concurrent chemoradiation therapy (CCRT) with esophageal self-expandable metal stents (SEMS) for the treatment of locally advanced esophageal cancer. Between January 2014 and December 2016, the data from 46 locally advanced esophageal cancer patients who received CCRT at our institution were retrospectively reviewed. Eight patients who received CCRT concomitant with SEMS placement (SEMS plus CCRT group) and thirty-eight patients who received CCRT without SEMS placement (CCRT group) were identified. The risk of developing esophageal fistula and the overall survival of the two groups were analyzed. The rate of esophageal fistula formation during or after CCRT was 87.5% in the SEMS plus CCRT group and 2.6% in the CCRT group. The median doses of radiotherapy in the SEMS plus CCRT group and the CCRT group were 47.5 Gy and 50 Gy, respectively. SEMS combined with CCRT was associated with a greater risk of esophageal fistula formation than CCRT alone (hazard ratio [HR], 72.30; 95% confidence interval [CI], 8.62-606.12; p < .001). The median overall survival times in the SEMS plus CCRT and CCRT groups were 6 months and 16 months, respectively. Overall survival was significantly worse in the SEMS plus CCRT group than in the CCRT group (HR, 5.72; 95% CI, 2.15-15.21; p < .001). CCRT concomitant with SEMS for locally advanced esophageal cancer results in earlier life-threatening morbidity and a higher mortality rate than treatment with CCRT alone. Further prospective and randomized studies are warranted to confirm these observations. Patients treated with SEMS placement followed by CCRT had higher risk of esophageal fistula formation and inferior overall survival rate compared with patients treated with CCRT alone. SEMS placement should be performed cautiously in patients who are scheduled to receive CCRT with curative intent.


Identification, Associated Factors, and Prognosis of Symptom Clusters in Taiwanese Patients With Heart Failure.
Patients with heart failure (HF) have multiple distressing symptoms that are associated with poor outcomes. These symptoms do not occur in isolation from each other but likely occur as discrete clusters that may prove helpful to clinicians trying to counsel patients about symptom monitoring and management. Defining common symptom clusters and determining the associations between symptom clusters and outcomes may improve patient management. The aim of this study was to define symptom clusters and their association with event-free survival in terms of cardiac hospitalization and all-cause mortality in patients with HF. Patients were recruited from outpatient HF clinics. Physical symptoms (dyspnea, fatigue, edema, sleeplessness, anorexia, and poor memory) were measured using the modified Pulmonary Function Status and Dyspnea Questionnaire and the Minnesota Living with Heart Failure Questionnaire. A two-stage cluster analysis was conducted to identify subgroups of patients based on the self-perceived severity of the six symptoms. The Kaplan-Meier survival curve and log-rank test were used to assess whether symptom clusters were associated with event-free survival through a 12-month follow-up. Two hundred fifty-eight patients (mean age = 61.2 ± 12.3 years, 75% male, 41% New York Heart Association class III/IV) participated. Three symptom clusters were identified based on the severity of symptoms. These clusters were called the nonsevere symptom cluster (all symptoms were rated with low severity), the typical severity symptom cluster (high level of severity for dyspnea and fatigue, low level of severity for edema, and moderate level of severity for all other symptoms), and the atypical severity symptom cluster (low level of severity for dyspnea and fatigue, high level of severity for edema, and moderate level of severity for all other symptoms). Symptom clusters were associated with event-free survival (p < .001). A post hoc comparison showed that the prognosis was better in the nonsevere symptom cluster than both the typical symptom (p < .001) and nontypical symptom (p < .001) clusters and that the prognoses for the latter two clusters did not differ significantly. Symptom clusters play an important role in the prognoses of patients with HF. Both patients and healthcare providers may use the information that is provided by this study to improve the surveillance and management of related symptoms.


Nonequilibrium Chromosome Looping via Molecular Slip Links.
We propose a model for the formation of chromatin loops based on the diffusive sliding of molecular slip links. These mimic the behavior of molecules like cohesin, which, along with the CTCF protein, stabilize loops which contribute to organizing the genome. By combining 3D Brownian dynamics simulations and 1D exactly solvable nonequilibrium models, we show that diffusive sliding is sufficient to account for the strong bias in favor of convergent CTCF-mediated chromosome loops observed experimentally. We also find that the diffusive motion of multiple slip links along chromatin is rectified by an intriguing ratchet effect that arises if slip links bind to the chromatin at a preferred "loading site." This emergent collective behavior favors the extrusion of loops which are much larger than the ones formed by single slip links.


Connecting allied health students to rural communities.
Statewide studies indicate a continuing shortfall of personnel in several allied health disciplines in rural Georgia. National trends indicate lagging enrollment in allied health education programs, suggesting that the workforce shortages will worsen. This article describes the efforts of the School of Allied Health Sciences at the Medical College of Georgia to increase allied health student participation in interdisciplinary health care services in rural areas of the state during fiscal years 2001-2003. Brief program description and results from survey data provided by the student participants, program administrators, and clinical site supervisors. Three-year totals indicate that 98 students (70 female, 28 male) participated and 42% reported low-income status. In line with the goals of the grant, the proportion of minority student participants steadily increased from 5% to 12% over the 3-year period. Rotation locations included 62 designated Health Professional Shortage Area counties, 71 federally designated Rural Health Clinics, and 6 Community Health Clinics. At the conclusion of the students' rural health care experience, 76% (55/72) responded positively when asked: If you had the opportunity, would you accept employment at the rotation health care site? The project appears to be positively affecting allied health students' perceptions and opinions of rural health practices and willingness to work in rural areas. Although long-term goals have yet to be accomplished, early indicators show benefits to the students and the community at-large, suggesting that the current program strategies are appropriate connectors between allied health students and rural communities.


Ulysses at jupiter: an overview of the encounter.
In February 1992, the Ulysses spacecraft flew through the giant magnetosphere of Jupiter. The primary objective of the encounter was to use the gravity field of Jupiter to redirect the spacecraft to the sun's polar regions, which will now be traversed in 1994 and 1995. However, the Ulysses scientific investigations were well suited to observations of the Jovian magnetosphere, and the encounter has resulted in a major contribution to our understanding of this complex and dynamic plasma environment. Among the more exciting results are (i) possible entry into the polar cap, (ii) the identification of magnetospheric ions originating from Jupiter's ionosphere, lo, and the solar wind, (iii) observation of longitudinal asymmetries in density and discrete wave-emitting regions of the lo plasma torus, (iv) the presence of counter-streaming ions and electrons, field-aligned currents, and energetic electron and radio bursts in the dusk sector on high-latitude magnetic field lines, and (v) the identification of the direction of the magnetic field in the dusk sector, which is indicative of tailward convection. This overview serves as an introduction to the accompanying reports that present the preliminary scientific findings. Aspects of the encounter that are common to all of the investigations, such as spacecraft capabilities, the flight path past Jupiter, and unique aspects of the encounter, are presented herein.


Predicting diabetes. Moving beyond impaired glucose tolerance.
We developed predictive models for type II diabetes using stepwise multiple logistic regression analyses of a cohort of 844 Mexican Americans and 641 non-Hispanic whites who were nondiabetic at baseline and who were then followed for 8 yr. Models were developed for the overall population and separately for each sex and ethnic group. For optimal models, the multiple logistic regression program selected potential risk factors from a panel of 5 categorical and 14 continuous demographic, anthropometric, metabolic, and hemodynamic variables. For reduced models, the list of candidate variables was restricted to those commonly used in ordinary clinical practice, i.e., skinfolds, and serum insulin and postural glucose load variables were excluded. For all models, the stepwise process selected a mixture of anthropometric, glucose, lipid, and hemodynamic variables. The top 15% of the risk continuum for each model was defined as high risk to compare the performance of the models with the performance of impaired glucose tolerance (15% prevalence) as a predictor of diabetes. The relative risk of being high risk ranged from 12.16 to 35.29, whereas the relative risk of having impaired glucose tolerance ranged from 7.11 to 10.0. The sensitivity of the multiple logistic regression models ranged from 67.7 to 83.3% compared with 56.5 to 62.1% for impaired glucose tolerance. The results indicate that multivariate predictive models perform at least as well, if not better than impaired glucose tolerance in predicting type II diabetes but need not require an oral glucose load. Moreover, the models highlight the complex metabolic and hemodynamic syndrome that precedes diabetes.


Mechanobiology of the cell wall - insights from tip-growing plant and fungal cells.
The cell wall (CW) is a thin and rigid layer encasing the membrane of all plant and fungal cells. It ensures mechanical integrity by bearing mechanical stresses derived from large cytoplasmic turgor pressure, contacts with growing neighbors or growth within restricted spaces. The CW is made of polysaccharides and proteins, but is dynamic in nature, changing composition and geometry during growth, reproduction or infection. Such continuous and often rapid remodeling entails risks of enhanced stress and consequent damages or fractures, raising the question of how the CW detects and measures surface mechanical stress and how it strengthens to ensure surface integrity? Although early studies in model fungal and plant cells have identified homeostatic pathways required for CW integrity, recent methodologies are now allowing the measurement of pressure and local mechanical properties of CWs in live cells, as well as addressing how forces and stresses can be detected at the CW surface, fostering the emergence of the field of CW mechanobiology. Here, using tip-growing cells of plants and fungi as case study models, we review recent progress on CW mechanosensation and mechanical regulation, and their implications for the control of cell growth, morphogenesis and survival.


Adaptive beam shaping by controlled thermal lensing in optical elements.
We describe an adaptive optical system for use as a tunable focusing element. The system provides adaptive beam shaping via controlled thermal lensing in the optical elements. The system is agile, remotely controllable, touch free, and vacuum compatible; it offers a wide dynamic range, aberration-free focal length tuning, and can provide both positive and negative lensing effects. Focusing is obtained through dynamic heating of an optical element by an external pump beam. The system is especially suitable for use in interferometric gravitational wave interferometers employing high laser power, allowing for in situ control of the laser modal properties and compensation for thermal lensing of the primary laser. Using CO(2) laser heating of fused-silica substrates, we demonstrate a focal length variable from infinity to 4.0 m, with a slope of 0.082 diopter/W of absorbed heat. For on-axis operation, no higher-order modes are introduced by the adaptive optical element. Theoretical modeling of the induced optical path change and predicted thermal lens agrees well with measurement.


DNA repair genotype interacts with arsenic exposure to increase bladder cancer risk.
Drinking water arsenic exposure has been associated with increased bladder cancer susceptibility. Epidemiologic and experimental data suggest a co-carcinogenic effect of arsenic with exposure to DNA damaging agents, such as cigarette smoke. Recent evidence further supports the hypothesis that genetic variation in DNA repair genes can modify the arsenic-cancer relationship, possibly because arsenic impairs DNA repair capacity. We tested this hypothesis in a population-based study of bladder cancer with XRCC3, ERCC2 genotype/haplotype and arsenic exposure data on 549 controls and 342 cases. Individual exposure to arsenic was determined in toenail samples by neutron activation. Gene-environment interaction with arsenic exposure was observed in relation to bladder cancer risk for a variant allele of the double-strand break repair gene XRCC3 T241M (adjusted OR 2.8 (1.1-7.3)) comparing to homozygous wild type among those in the top arsenic exposure decile (interaction p-value 0.01). Haplotype analysis confirmed the association of the XRCC3 241. Thus, double-strand break repair genotype may enhance arsenic associated bladder cancer susceptibility in the U.S. population.


Outcome of recipients of human leukocyte antigen incompatible kidney transplants who underwent desensitization at King Fahad Specialist Hospital, Dammam, Saudi Arabia.
In patients whom are highly sensitized immunologically, the benefit of kidney transplantation can be extended to this population through the utilization of organs from human leukocyte antigen incompatible (HLAi) donors. This retrospective observational study was designed to identify the incidence and predictors of acute antibody-mediated rejection/acute cellular rejection (AMR/ACR) in our kidney recipients from living kidney donors (sensitized and those with low immunologic risk). This single-center study has been conducted at King Fahad Specialist Hospital, Dammam (KFSH-D), Saudi Arabia; during the period of September 2008- August 2013. All eligible recipients of living donor kidneys during the study period were included (n = 213) in the study. Over 60% of patients in the study were females. Thirty of the 213 kidneys were from HLAi donors. During the follow-up period (median follow-up time = 16 months; 3-27 months), the incidence rate of ACR among HLA compatible (HLAc) and HLAi groups was 22.2% and 16.7%, respectively (P >0.05). The incidence rate of AMR was 2.6% in HLAc group and 16.7%in the HLAi group (P<0.05). The significantly higher incidence of AMR in HLAi group can be explained by the presence of the donor-specific antibodies in weak titers. These results are consistent with studies from similar populations in published literature. However, the relatively small number and short duration of the study are considered, and longer follow-up of this population will be needed for conclusions on the sustainability of our findings.


The PROMETHEUS bundled payment experiment: slow start shows problems in implementing new payment models.
Fee-for-service payment is blamed for many of the problems observed in the US health care system. One of the leading alternative payment models proposed in the Affordable Care Act of 2010 is bundled payment, which provides payment for all of the care a patient needs over the course of a defined clinical episode, instead of paying for each discrete service. We evaluated the initial "road test" of PROMETHEUS Payment, one of several bundled payment pilot projects. The project has faced substantial implementation challenges, and none of the three pilot sites had executed contracts or made bundled payments as of May 2011. The pilots have taken longer to set up than expected, primarily because of the complexity of the payment model and the fact that it builds on the existing fee-for-service payment system and other complexities of health care. Participants continue to see promise and value in the bundled payment model, but the pilot results suggest that the desired benefits of this and other payment reforms may take time and considerable effort to materialize.


Compounds Isolated from Wikstroemia taiwanensis Regulate Bone Remodeling by Modulating Osteoblast and Osteoclast Activities.
Bone remodeling, a dynamic process in which bone formation by osteoblast is preceded by bone resorption by osteoclast, is a vital physiological process for maintaining bone mass and strength, imbalances in which could precipitate osteoporosis. Due to the unilateral mechanism of the existing bone remodeling drugs, identifying compounds that could regulate the balance between osteoclast and osteoblast could improve the treatment of osteoporosis. Here, we show that compounds isolated from Wikstroemia taiwanensis modulate osteoclast and osteoblast activities. Specifically, astragalin (1) and kaempferol 3-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (2), besides increasing mineral deposition, increased alkaline phosphatase activity (137.2% for 1 and 115.8% for 2) and ESR-α expression (112.8% for 1 and 122.5% for 2) in primary human osteoblasts. In contrast, compounds 1, 2, 3, and 5 inhibited tartrate-resistant acid phosphatase (TRAP) activity in receptor activator of nuclear factor-κB ligand-induced osteoclasts by 40.8, 17.1, 25.9, and 14.5% and also decreased the number of TRAP-positive cells by 51.6, 26.8, 20.5, and 18.6%, respectively. Our findings, therefore, showed that compounds isolated from W. taiwanensis could increase osteoblast activity while simultaneously decreasing osteoclast activity, and hence, warrant further evaluation for development as anti-osteoporosis agents.


Exposure from the Chernobyl accident had adverse effects on erythrocytes, leukocytes, and, platelets in children in the Narodichesky region, Ukraine: a 6-year follow-up study.
After the Chernobyl nuclear accident on April 26, 1986, all children in the contaminated territory of the Narodichesky region, Zhitomir Oblast, Ukraine, were obliged to participate in a yearly medical examination. We present the results from these examinations for the years 1993 to 1998. Since the hematopoietic system is an important target, we investigated the association between residential soil density of 137Caesium (137Cs) and hemoglobin concentration, and erythrocyte, platelet, and leukocyte counts in 1,251 children, using 4,989 repeated measurements taken from 1993 to 1998. Soil contamination measurements from 38 settlements were used as exposures. Blood counts were conducted using the same auto-analyzer in all investigations for all years. We used linear mixed models to compensate for the repeated measurements of each child over the six year period. We estimated the adjusted means for all markers, controlling for potential confounders. Data show a statistically significant reduction in red and white blood cell counts, platelet counts and hemoglobin with increasing residential 137Cs soil contamination. Over the six-year observation period, hematologic markers did improve. In children with the higher exposure who were born before the accident, this improvement was more pronounced for platelet counts, and less for red blood cells and hemoglobin. There was no exposurextime interaction for white blood cell counts and not in 702 children who were born after the accident. The initial exposure gradient persisted in this sub-sample of children. The study is the first longitudinal analysis from a large cohort of children after the Chernobyl accident. The findings suggest persistent adverse hematological effects associated with residential 137Cs exposure.


PPP2R2C loss promotes castration-resistance and is associated with increased prostate cancer-specific mortality.
Metastatic prostate cancers generally rely on androgen receptor (AR) signaling for growth and survival, even following systemic androgen-deprivation therapy (ADT). However, recent evidence suggests that some advanced prostate cancers escape ADT by using signaling programs and growth factors that bypass canonical AR ligand-mediated mechanisms. We used an in vitro high-throughput RNA interference (RNAi) screen to identify pathways in androgen-dependent prostate cancer cell lines whose loss-of-function promotes androgen ligand-independent growth. We identified 40 genes where knockdown promoted proliferation of both LNCaP and VCaP prostate cancer cells in the absence of androgen. Of these, 14 were downregulated in primary and metastatic prostate cancer, including two subunits of the protein phosphatase 2 (PP2A) holoenzyme complex: PPP2R1A, a structural subunit with known tumor-suppressor properties in several tumor types; and PPP2R2C, a PP2A substrate-binding regulatory subunit that has not been previously identified as a tumor suppressor. We show that loss of PPP2R2C promotes androgen ligand depletion-resistant prostate cancer growth without altering AR expression or canonical AR-regulated gene expression. Furthermore, cell proliferation induced by PPP2R2C loss was not inhibited by the AR antagonist MDV3100, indicating that PPP2R2C loss may promote growth independently of known AR-mediated transcriptional programs. Immunohistochemical analysis of PPP2R2C protein levels in primary prostate tumors determined that low PPP2R2C expression significantly associated with an increased likelihood of cancer recurrence and cancer-specific mortality. These findings provide insights into mechanisms by which prostate cancers resist AR-pathway suppression and support inhibiting PPP2R2C complexes or the growth pathway(s) activated by PPP2R2C as a therapeutic strategy.


Prescribing medication errors in hospitalised patients: a prospective study.
The aims of this prospective study were to determine the incidence and types of prescribing medication errors and ways to prevent them from reaching patients. Data were collected from 4951 prescriptions over a 25 week period in 2002. Medication errors were classified as: incorrect dose, incorrect dose interval, duplication of therapy and drug interactions. The medical record analysis was used to compare prescribing with Croatian literature drug data and AHFS first Web version 2 (American Society of Health System Pharmacists). The incidence of medication errors in the entire sample, including all potential drug interactions, was 14.7%. However, as only 8 interactions (out of 356 potentially possible interactions) were assessed as clinically significant, then the total number of all types of medication errors was 379. This resulted in an incidence of 7.7%. Dosage errors were the most frequent errors, followed by incorrect interval, drug duplication and drug interaction. The difference between the incidence of potentially possible and clinically significant drug interactions was quite large (7.2 vs. 0.2%). Thus, a critical attitude is necessary when evaluating available data on drug interactions. Our findings point to the need of systematic control of prescribed therapies, which could be ensured by the application of the Unit Dose Drug Distribution System. A medication errors reporting program should be established both at the hospital and at national levels in Croatia.


Radio over fiber transceiver employing phase modulation of an optical broadband source.
This paper proposes a low-cost RoF transceiver for multichannel SCM/WDM signal distribution suitable for future broadband access networks. The transceiver is based on the phase modulation of an optical broadband source centered at third transmission window. Prior to phase modulation the optical broadband source output signal is launched into a Mach-Zehnder interferometer structure, as key device enabling radio signals propagation over the optical link. Furthermore, an optical CWDM is employed to create a multichannel scenario by performing the spectral slicing of the modulated optical signal into a number of channels each one conveying the information from the central office to different base stations. The operation range is up to 20 GHz with a modulation bandwidth around of 500 MHz. Experimental results of the transmission of SCM QPSK and 64-QAM data through 20 Km of SMF exhibit good EVM results in the operative range determined by the phase-to-intensity conversion process. The proposed approach shows a great suitability for WDM networks based on RoF signal transport and also represents a cost-effective solution for passive optical networks.


Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema.
Brain oedema is a life-threatening complication of various neurological conditions. Understanding molecular mechanisms of brain volume regulation is critical for therapy development. Unique insight comes from monogenic diseases characterized by chronic brain oedema, of which megalencephalic leukoencephalopathy with subcortical cysts (MLC) is the prototype. Variants in MLC1 or GLIALCAM, encoding proteins involved in astrocyte volume regulation, are the main causes of MLC. In some patients, the genetic cause remains unknown. We performed genetic studies to identify novel gene variants in MLC patients, diagnosed by clinical and MRI features, without MLC1 or GLIALCAM variants. We determined subcellular localization of the related novel proteins in cells and in human brain tissue. We investigated functional consequences of the newly identified variants on volume regulation pathways using cell volume measurements, biochemical analysis and electrophysiology. We identified a novel homozygous variant in AQP4, encoding the water channel aquaporin-4, in two siblings, and two de novo heterozygous variants in GPRC5B, encoding the orphan G protein-coupled receptor GPRC5B, in three unrelated patients. The AQP4 variant disrupts membrane localization and thereby channel function. GPRC5B, like MLC1, GlialCAM and aquaporin-4, is expressed in astrocyte endfeet in human brain. Cell volume regulation is disrupted in GPRC5B patient-derived lymphoblasts. GPRC5B functionally interacts with ion channels involved in astrocyte volume regulation. In conclusion, we identify aquaporin-4 and GPRC5B as old and new players in genetic brain oedema. Our findings shed light on the protein complex involved in astrocyte volume regulation and identify GPRC5B as novel potentially druggable target for treating brain oedema.


Acute effects of Sceletium tortuosum (Zembrin), a dual 5-HT reuptake and PDE4 inhibitor, in the human amygdala and its connection to the hypothalamus.
The South African endemic plant Sceletium tortuosum has a long history of traditional use as a masticatory and medicine by San and Khoikhoi people and subsequently by European colonial farmers as a psychotropic in tincture form. Over the past decade, the plant has attracted increasing attention for its possible applications in promoting a sense of wellbeing and relieving stress in healthy individuals and for treating clinical anxiety and depression. The pharmacological actions of a standardized extract of the plant (Zembrin) have been reported to be dual PDE4 inhibition and 5-HT reuptake inhibition, a combination that has been argued to offer potential therapeutic advantages. Here we tested the acute effects of Zembrin administration in a pharmaco-fMRI study focused on anxiety-related activity in the amygdala and its connected neurocircuitry. In a double-blind, placebo-controlled, cross-over design, 16 healthy participants were scanned during performance in a perceptual-load and an emotion-matching task. Amygdala reactivity to fearful faces under low perceptual load conditions was attenuated after a single 25 mg dose of Zembrin. Follow-up connectivity analysis on the emotion-matching task showed that amygdala-hypothalamus coupling was also reduced. These results demonstrate, for the first time, the attenuating effects of S. tortuosum on the threat circuitry of the human brain and provide supporting evidence that the dual 5-HT reuptake inhibition and PDE4 inhibition of this extract might have anxiolytic potential by attenuating subcortical threat responsivity.


The prognostic and predictive value of Tregs and tumor immune subtypes in postmenopausal, hormone receptor-positive breast cancer patients treated with adjuvant endocrine therapy: a Dutch TEAM study analysis.
Evidence exists for an immunomodulatory effect of endocrine therapy in hormone receptor-positive (HR+ve) breast cancer (BC). Therefore, the aim of this study was to define the prognostic and predictive value of tumor immune markers and the tumor immune profile in HR+ve BC, treated with different endocrine treatment regimens. 2,596 Dutch TEAM patients were treated with 5 years of adjuvant hormonal treatment, randomly assigned to different regimens: 5 years of exemestane or sequential treatment (2.5 years of tamoxifen-2.5 years of exemestane). Immunohistochemistry was performed for HLA class I, HLA-E, HLA-G, and FoxP3. Tumor immune subtypes (IS) (low, intermediate & high immune susceptible) were determined by the effect size of mono-immune markers on relapse rate. Patients on sequential treatment with high level of tumor-infiltrating FoxP3+ cells had significant (p = 0.019, HR 0.729, 95% CI 0.560-0.949) better OS. Significant interaction for endocrine treatment and FoxP3+ presence was seen (OS p < 0.001). Tumor IS were only of prognostic value for the sequentially endocrine-treated patients (RFP: p = 0.035, HR intermediate IS 1.420, 95% CI 0.878-2.297; HR low IS 1.657, 95% CI 1.131-2.428; BCSS: p = 0.002, HR intermediate IS 2.486, 95% CI 1.375-4.495; HR low IS 2.422, 95% CI 1.439-4.076; and OS: p = 0.005, HR intermediate IS 1.509, 95% CI 0.950-2.395; HR low IS 1.848, 95% CI 1.277-2.675). Tregs and the tumor IS presented in this study harbor prognostic value for sequentially endocrine-treated HR+ve postmenopausal BC patients, but not for solely exemestane-treated patients. Therefore, these markers could be used as a clinical risk stratification tool to guide adjuvant treatment in this BC population.


Microbial carriage state of peripheral blood dendritic cells (DCs) in chronic periodontitis influences DC differentiation, atherogenic potential.
The low-grade oral infection chronic periodontitis (CP) has been implicated in coronary artery disease risk, but the mechanisms are unclear. In this study, a pathophysiological role for blood dendritic cells (DCs) in systemic dissemination of oral mucosal pathogens to atherosclerotic plaques was investigated in humans. The frequency and microbiome of CD19(-)BDCA-1(+)DC-SIGN(+) blood myeloid DCs (mDCs) were analyzed in CP subjects with or without existing acute coronary syndrome and in healthy controls. FACS analysis revealed a significant increase in blood mDCs in the following order: healthy controls < CP < acute coronary syndrome/CP. Analysis of the blood mDC microbiome by 16S rDNA sequencing showed Porphyromonas gingivalis and other species, including (cultivable) Burkholderia cepacia. The mDC carriage rate with P. gingivalis correlated with oral carriage rate and with serologic exposure to P. gingivalis in CP subjects. Intervention (local debridement) to elicit a bacteremia increased the mDC carriage rate and frequency in vivo. In vitro studies established that P. gingivalis enhanced by 28% the differentiation of monocytes into immature mDCs; moreover, mDCs secreted high levels of matrix metalloproteinase-9 and upregulated C1q, heat shock protein 60, heat shock protein 70, CCR2, and CXCL16 transcripts in response to P. gingivalis in a fimbriae-dependent manner. Moreover, the survival of the anaerobe P. gingivalis under aerobic conditions was enhanced when within mDCs. Immunofluorescence analysis of oral mucosa and atherosclerotic plaques demonstrate infiltration with mDCs, colocalized with P. gingivalis. Our results suggest a role for blood mDCs in harboring and disseminating pathogens from oral mucosa to atherosclerosis plaques, which may provide key signals for mDC differentiation and atherogenic conversion.


Neurosurgical management of intractable rolandic epilepsy in children: role of resection in eloquent cortex. Clinical article.
The authors undertook this study to review their experience with cortical resections in the rolandic region in children with intractable epilepsy. The authors retrospectively reviewed the medical records obtained in 22 children with intractable epilepsy arising from the rolandic region. All patients underwent preoperative electroencephalography (EEG), MR imaging, prolonged video-EEG recordings, functional MR imaging, magnetoencephalography, and in some instances PET/SPECT studies. In 21 patients invasive subdural grid and depth electrode monitoring was performed. Resection of the epileptogenic zones in the rolandic region was undertaken in all cases. Seizure outcome was graded according to the Engel classification. Functional outcome was determined using validated outcome scores. There were 10 girls and 12 boys, whose mean age at seizure onset was 3.2 years. The mean age at surgery was 10 years. Seizure duration prior to surgery was a mean of 7.4 years. Nine patients had preoperative hemiparesis. Neuropsychological testing revealed impairment in some domains in 19 patients in whom evaluation was possible. Magnetic resonance imaging abnormalities were identified in 19 patients. Magnetoencephalography was performed in all patients and showed perirolandic spike clusters on the affected side in 20 patients. The mean duration of invasive monitoring was 4.2 days. The mean number of seizures during the period of invasive monitoring was 17. All patients underwent resection that involved primary motor and/or sensory cortex. The most common pathological entity encountered was cortical dysplasia, in 13 children. Immediately postoperatively, 20 patients had differing degrees of hemiparesis, from mild to severe. The hemiparesis improved in all affected patients by 3-6 months postoperatively. With a mean follow-up of 4.1 years (minimum 2 years), seizure outcome in 14 children (64%) was Engel Class I and seizure outcome in 4 (18%) was Engel Class II. In this series, seizure outcome following perirolandic resection was intimately related to the child's age at the time of surgery. By univariate logistic regression analysis, age at surgery was a statistically significant factor predicting seizure outcome (p < 0.024). Resection of rolandic cortex for intractable epilepsy is possible with expected morbidity. Accurate mapping of regions of functional cortex and epileptogenic zones may lead to improved seizure outcome in children with intractable rolandic epilepsy. It is important to counsel patients and families preoperatively to prepare them for possible worsened functional outcome involving motor, sensory and/or language pathways.


Commentary: using medical student case presentations to help faculty learn to be better advisers.
The case presentation is a time-honored tradition in clinical medicine, and medical journals and national conferences have provided a forum for this type of scholarship for more than a century. Case presentations can also be used by educators as a means to understand challenging learner experiences, and by doing so, lead to advances in the practice of medical education. Medical school faculty are asked to serve in student advisor roles, yet best practices for student advising are not known. Unlike clinicians, who often discuss difficult patient cases, medical educators do not typically have opportunities to discuss challenging student cases to learn how best to support trainees. In this commentary, the authors-from the Johns Hopkins University School of Medicine Colleges Advisory Program (CAP), a longitudinal advising program with the goal of promoting personal and professional development of students-describe the novel quarterly Advisory Case Conference, where medical student cases can be confidentially presented and discussed by faculty advisors, along with relevant literature reviews, to enhance faculty advising skills for students. As medical student advising needs often vary, CAP advisors employ adult learning principles and emphasize shared responsibility between advisor and advisee as keys to successful advising. Unlike traditional clinical case conferences, the Advising Case Conference format encourages advisors to share perspectives about the cases by working in small groups to exchange ideas and role-play solutions. This model may be applicable to other schools or training programs wishing to enhance faculty advising skills.


Allicin induces apoptosis in gastric cancer cells through activation of both extrinsic and intrinsic pathways.
Allicin is an active compound derived from garlic that has been shown to have antitumor properties in vitro. The current study was designed to explore the effects and the underlying mechanism of allicin on gastric cancer cells. The MTT assay was used to detect cell viability. Transmission electron microscopy, Rh123 and propidium iodide staining, annexin V/FITC assay and the mitochondrial membrane potential were used to assess for the presence of apoptosis. Immunocytochemistry, western blot analysis, and Q-RT-PCR were used to detect gene expression. We found that allicin reduced cell viability in a dose- and time-dependent manner, partly through induction of apoptosis in gastric cancer cells. At the molecular level, allicin induced cytochrome c release from the mitochondria and increased caspase-3, -8, and -9 activation, with concomitant upregulation of bax and fas expression in the tumor cells. Allicin treatment inhibited proliferation and induced apoptosis in SGC-7901 cancer cells. Both intrinsic mitochondrial and extrinsic Fas/FasL-mediated pathways of apoptosis occur simultaneously in SGC-7901 cells following allicin treatment. Data from the current study demonstrated that allicin should be further investigated as a novel cancer preventive or therapeutic agent in control of gastric cancer, with potential uses in other tumor types.


What do we know about older adults and HIV? A review of social and behavioral literature.
The fastest growing segment of the United States HIV population is people aged 50 and older. This heterogeneous group includes people with diverse pathways into HIV positive status in later life, including aging with the disease as well as later life-acquired infections. As people with HIV live into older ages, solving problems of successful secondary prevention and ongoing treatment requires more specific knowledge of the particular aging-related contextual sociocultural, psychosocial, and personal factors salient to the situations of persons living with HIV. Greater knowledge of these factors will help solve challenges to reducing psychological burden and promoting health maintenance for people with HIV. Yet, the current literature on aging and HIV remains nascent. To assess the state of knowledge of the sociocultural and behavioral factors associated with aging with HIV, we conducted a systematic critical content review of peer-reviewed social and behavioral research on aging and HIV to answer the question, "How have older age, and social, cultural, and behavioral aspects of the intersection of HIV and age been addressed in the literature?" We searched First Search, Proquest, Psych Info, Pub Med, Wilson Select Plus, and World Cat and identified 1549 articles. We then reviewed these to select peer-reviewed articles reporting results of research on the social and behavioral aspects of living with HIV at age 50 and older. Fifty-eight publications were identified that met study inclusion criteria. While few publications reported clear age-related differences, there were significant ethnic differences in living with HIV in later life and also differences among older people when groups were defined by mode of transmission. Findings are discussed in light of constructs from gerontology which may contribute to clarifying how later life, life course stage, and psychological development intersect with, influence, and are influenced by HIV disease and long-term anti-retroviral therapy use.


Carrier risk status changes resulting from mutation testing in hereditary non-polyposis colorectal cancer and hereditary breast-ovarian cancer.
In hereditary cancer syndrome families with an identified cancer associated mutation, mutation testing changes the carrier risk status of the tested person and may change the carrier risk status of relatives. This study aimed to describe the change in the distribution of carrier risk status resulting from testing in hereditary breast-ovarian cancer (HBOC) and hereditary non-polyposis colorectal cancer (HNPCC) families. This was an observational cohort study. The cohort included members of 75 HBOC and 47 HNPCC families. Of the 10 910 cohort members, 1408 were tested for a mutation and learned their test results. Carrier risk for all cohort members was assessed before and after mutation testing. There was a change in carrier risk status in 2906 subjects after testing of 1408 family members. The most common type of carrier risk change, from at risk to non-carrier status, accounted for 77% of the risk changes; 12% were a change to known carrier status from a lower risk. Sixty percent of persons with a carrier risk status change were not themselves tested; their risk status changed because of a relative's test result. Carrier risk status changes from uncertainty to certainty (that is, to carrier or to non-carrier) account for 89% of risk changes resulting from testing. These risk changes affect cancer prevention recommendations, most commonly reducing their burden. Current practices do not ensure that untested family members are informed about changes in their carrier risk status which result from mutation testing of their relatives.


Acetylation polymorphism and leprosy.
The sulfones are the drug of choice in the treatment of leprosy, with dapsone as the clear favorite. The major route for dapsone metabolism leading to its inactivation and excretion is via acetylation by hepatic N-acetyl transferase (NAT), as is the case with isoniazid (INH) and sulfamethazine (SMZ). The enzyme is known to exhibit genetic polymorphism. The object of the present study is mainly to determine the incidence of acetylator phenotype in a population of leprosy patients with a view to evaluating the degree of association, if any, between phenotype and the disease. Obviously a knowledge of the incidence of the phenotypes may provide a valuable contribution to the institution of more rational and successful therapy. In the normal or control subjects, as well as in the leprosy patients, the frequency distribution histograms of the percentage acetylsulfamethazine in urine and serum samples are bimodal, and this indicates the existence of a genetic polymorphism. Based on the bimodality, individuals were classified as either "rapid" or "slow" acetylators, and the incidence of the slow acetylator phenotype of about 51% was observed in the leprosy population. This gives a relatively high incidence of the allele controlling the slow acetylator (q = 0.73). Although there is evidence that the mean percentage of SMZ acetylated in leprosy patients of the slow acetylator phenotype is significantly higher than that observed for the same phenotype in the controls (t = 4.86, P less than 0.02), statistical analyses show that there is no association between the slow acetylator phenotype and the disease.(ABSTRACT TRUNCATED AT 250 WORDS)